This is an application for a K08 Career Development Award for Carlos Alvarez, an Assistant Professor and clinical pharmacist at Texas Tech University Health Sciences Center School of Pharmacy. His long-term career goal is to be an internationally known expert and independent investigator in the pharmacoepidemiology of therapeutic agents used in patients with type 2 diabetes and chronic kidney disease. The career development aims of this K08 application are to support training in: Aim 1) pharmacoepidemiology, Aim 2) health services research, and Aim 3) analysis of large, complex national databases. This career development award will also support Dr. Alvarez's path to independence. To achieve this goal, Dr. Alvarez has assembled a multidisciplinary mentoring and advisory team with significant experience in extramurally funded clinical research. Chronic kidney disease (CKD) is a common and well known complication of type 2 diabetes (T2DM). This complication often restricts providers from prescribing metformin, a glucose-lowering agent with known morbidity and mortality benefits in patients with T2DM. This FDA labeled contraindication for metformin using arbitrary serum creatinine cut-points in patients with T2DM and CKD is not evidence based and often necessitates prescribers to initiate or switch patients to other glucose-lowering agents with worse adverse event profiles or that have been associated with poor cardiac outcomes. Guidance in other countries do not endorse the FDA contraindication and allows for metformin use in patients with mild to moderate CKD as measured by estimated glomerular filtration rate. This recommendation is also not based in evidence. Thus, the safety and effectiveness of metformin in patients with T2DM and CKD is largely unknown. Dr. Alvarez's research will focus on determining the safety and effectiveness through three specific research aims. In Aim 1 he will determine patterns of metformin use in patients with T2DM and CKD. He will analyze complex administrative and clinical data from the national VA database hosted by VINCI. Patterns identified in Aim 1 will inform him of the variables that should be further tested in Aims 2 and 3. Aim 2 will examine associations of adverse events for metformin and other glucose-lowering agents. Specifically, he will study incident hospitalizations for lactic acidosis and primary hospitalizations or emergency department visits for hypoglycemia. In Aim 3, Dr. Alvarez will assess the relationship between metformin and the development of microvascular and macrovascular outcomes. Microvascular outcomes assessed will be the development of proliferative diabetic retinopathy and progression of kidney disease. Macrovascular outcomes will be measured as a composite of non-fatal stroke, acute myocardial infarction, non-traumatic lower extremity amputation and cardiovascular disease death. He will also compare glycemic control between patients prescribed metformin and those on other glucose-lowering agents. Innovative techniques such as combination high-dimensional propensity score and instrumental variable modeling will be used in Aims 2 and 3 to reduce bias often encountered in observational research. The research will form the basis for an R01 or equivalent application to compare metformin usage patterns, safety and effectiveness in patients with type 2 diabetes and chronic kidney disease between those treated in the VA system and the United Kingdom.